Epoxide hydrolases are a group of enzymes that catalyze the addition of water to an epoxide, resulting in a vicinal diol (Hammock et al (1997) in Comprehensive Toxicology: Biotransformation (Elsevier, New York), pp. 283-305). Several types of epoxide hydrolases have been characterized in mammals including soluble epoxide hydrolase (sEH), also known as cytosolic epoxide hydrolase, cholesterol epoxide hydrolase, leukotriene A4 (LTA4) hydrolase, hepoxilin epoxide hydrolase and microsomal epoxide hydrolase (mEH) (Fretland and Omiecinski, Chemico-Biological Interactions, 129: 41-59 (2000)). Epoxide hydrolases have been found in a variety of tissues in vertebrates including heart, kidney and liver.
sEH in humans (hsEH, EPHX2) is a bifunctional homodimeric enzyme located in both cytosol and peroxisomes with hydrolase and phosphatase activity (Newman et al, Prog. Lipid Res, 44: 1-51(2005)). Specifically the C terminus hydrolase motif of sEH transforms four regioisomers of epoxyeicosatrienoic acids (EETs), namely 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs). The products generated by hydrolysis of these substrates are the dihydroxyeicosatrienoic acids or DHETS, 5,6-, 8,9-, 11,12-, and 14,15-dihydroxyeicosatrienoic acid respectively, whereby the biological effects of EETs are diminished or eliminated (Yu et al., Circ. Res, 87: 992-7 (2000)). Also known to be substrates are epoxides of linoleic acid known as leukotoxin or isoleukotoxin. Both the EETs and the leukotoxins are generated by members of the cytochrome P450 monooxygenase family (Capdevila et al., J. Lipid Res., 41: 163-181 (2000)).
The structural requirements for substrates of sEH have recently been described (Morisseau et al., Biochem. Pharmacol. 63:1599-1608 (2002)) and the crystal structure, as well as structures of co-crystals with inhibitors determined (Argiriadi et al., Proc. Natl. Acad. Sci. USA 96: 10637-10642 (1999)). A variety of inhibitors of sEH have also been described (Mullin and Hammock, Arch. Biochem. Biophys. 216:423-439 (1982), Morisseau et al., Proc. Natl. Acad. Sci. USA 96:8849-8854 (1999), McElroy et al., J. Med. Chem. 46:1066-1080 (2003)). A phosphatase activity for phosphorylated forms of hydroxy unsaturated fatty acids has recently been described for soluble epoxide hydrolase, making this a bifunctional enzyme (Newman et al., Proc. Natl. Acad. Sci. USA 100:1558-1563 (2003)).
The physiological role of EETs has best been established in vasodilation of vascular beds. Evidence has accumulated that EETs in fact function as endothelium-derived hyperpolarizing factors or EDHFs (Campbell et al., Circ. Res. 78:415-423 (1996)). EETs are formed in endothelial cells, induce vasodilation in vascular smooth muscle cells by a mechanism that results in activation of “maxi K” potassium channels with attendant hyperpolarization and relaxation (Hu and Kim, Eur. J. Pharmacol. 230:215-221 (1993)). It has been shown that 14,15-EET exerts its physiological effects by binding to cell surface receptors that are regulated by intracellular cyclic AMP and by a signal transduction mechanism involving protein kinase A (Wong et al., J. Lipid Med. Cell Signal. 16:155-169 (1997)). More recently, this EET dependent relaxation in coronary smooth muscle was demonstrated to occur through a guanine nucleotide binding protein, Gsα, accompanied by ADP-ribosylation (Li et al., Circ. Res. 85:349-56 (1999)). Alternatively, the cation channel TRPV4, has recently been shown to be activated by 5,6-EET in mouse aorta vascular endothelial cells (Watanabe et al., Nature 424:434-438 (2003)). This has generated interest in EETs and soluble epoxide hydrolase as targets for antihypertensives. Indeed, male sEH knockout mice have reduced blood pressure as compared to wild type controls (Sinal et al., J. Biol. Chem. 275:40504-40510 (2000)). Furthermore, inhibition of sEH in spontaneously hypertensive rats caused a reduction in blood pressure (Yu et al., Circ. Res. 87:992-998 (2000)).
EET mimics or pharmacological interventions to either increase the synthesis of EETs or prevent degradation of EETs (with reduced levels of DHETs) have been proposed as a potential therapeutic strategy for a variety of diseases. It has been further postulated that inhibition of the NF-kappaB pathway resulting from sEH inhibition could have therapeutic effects with regard to a variety of disease states (Shen, Expert Opin. Ther. Patents, 20(7): 941-956 (2010)).
sEH inhibitors were demonstrated as useful for the treatment of inflammatory disease states, e.g. rheumatoid arthritis, and cardiovascular disease states, such as hypertension, myocardial infarction, renal diseases and ischemic stroke (Fang et al, Drugs of the Future, 34(7): 579-585 (2009), Shen, Expert Opin. Ther. Patents, 20(7): 941-956 (2010), US20070117782; WO2003/002555).
A further indication of sEH inhibitors was claimed to be nephropathy in patients with type II diabetes (US20090018092 and WO2005/089380).
Inhibitors of sEH can be useful for the treatment of genitourinary disease states, including smooth muscle disorder states such as erectile dysfunction, overactive bladder, uterine contractions and irritable bowel syndrome (US20090270452, US2009082402, WO2008/074678).
sEH inhibitors were proposed to reduce pulmonary infiltration by neutrophils (US20050222252, WO2005/094373) and appeared to be synergistic in reducing the number of neutrophils in lung indicating that sEH inhibitors may be useful to treat obstructive pulmonary disease states, restrictive airway disease states and asthma (Shen, Expert Opin. Ther. Patents, 20(7): 941-956 (2010), US20050222252).
sEH inhibitors were also claimed to be useful for the treatment of neuropathic pain (WO2009/062073).
sEH inhibitors were further reported to be useful for the treatment of metabolic syndromes, including obesity, hypertension, diabetes and hypercholesterolemia (Shen, Expert Opin. Ther. Patents, 20(7): 941-956 (2010), US20080221105).
It appeared that sEH inhibitors are effective in the treatment of T-lymphocyte mediated immunological and autoimmunological disease states (WO2000/23060).
Further studies revealed the effect of sEH inhibitors on the reduction of damage from stroke (US20060148744).
Objects of the present invention are new compounds of Formula I, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, their use for the treatment of disease states mediated by sEH, including genitourinary disease states, pain disease states, respiratory disease states, cardiovascular disease states, metabolic disease states, neurological disease states, immunological disease states, inflammatory disease states, cancer, nephropathy, stroke, endothelial dysfunction, prevention of ischemic events and end organ protection, and medicaments based on a compound in accordance with the invention in the control or prevention of illnesses.